Hypoglycemia is the major obstacle preventing the benefits associated with intensive insulin therapy in individuals with diabetes. Low glucose levels can lead to cognitive impairment and even brain damage. Therefore, mechanisms to reduce these deleterious effects are important to elucidate. Brain glycogen, the only significant energy store in the brain, has been proposed to play a role in these processes. The overall objective of this proposal is to determine the importance of brain glycogen in memory formation and neuroprotection under hypoglycemic conditions. Genetically engineered mice with deficient brain glycogen stores will be used to address the following aims: Aim 1. Does reduced brain glycogen impair cognitive function during hypoglycemia? Hypoglycemic mice will be subjected to various learning paradigms to monitor both performance and proteins involved in memory consolidation. Aim 2. Does brain glycogen provide protection against hypoglycemia-induced neuronal cell death? Mice will be subjected to insulin- induced hypoglycemia to monitor susceptibility to, and mechanism of, neuronal cell death. These studies are expected to improve our understanding of the role of brain glycogen in mammals for cognitive function and neuroprotection during hypoglycemia. Should manipulation of brain glycogen levels prove beneficial, a small molecule regulator of glycogen metabolism in the brain could perhaps be a useful therapeutic for subjects with insulin-treated diabetes and subjects with mutations in glycogen synthase.